The University of Southampton
University of Southampton Institutional Repository

Mycobacterium tuberculosis senses host Interferon-gamma via the membrane protein MmpL10

Mycobacterium tuberculosis senses host Interferon-gamma via the membrane protein MmpL10
Mycobacterium tuberculosis senses host Interferon-gamma via the membrane protein MmpL10
Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens and remains a leading cause of death from infectious disease. Interferon-γ (IFN-γ) is a central regulator of the immune defense against Mtb. Several cytokines have been shown to increase virulence of other bacterial pathogens, leading us to investigate whether IFN-γ has a direct effect on Mtb. We found that both recombinant and T-cell derived IFN-γ rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was also observed in clinical strains, but not in the vaccine strain Bacillus Calmette–Guérin (BCG), and did not occur for other cytokines tested, including TNF-α. IFN-γ binds to the cell surface of intact Mtb, but not BCG, whilst TNF-α binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-γ binding and the OCR response was absent in a Mtb Δmmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-γ exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-γ resulted in sterilization of bacilli treated with isoniazid (INH), indicating clearance of phenotypically resistant bacteria that persist in the presence of INH alone. Our data suggest a novel mechanism allowing Mtb to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies.

One-Sentence Summary IFN-γ is a critical component of effective immune defense in human tuberculosis yet its causative agent, Mycobacterium tuberculosis it able to sense this cytokine and increase virulence and respiration in response.
2399-3642
Ahmed, Mohamed
3e7876a3-25bb-4512-9172-b6d79a7e9516
Mackenzie, Jared
f0352cab-ab6a-40e0-98b6-970b09e9b854
Krause, Robert
c8a1efd5-d86e-4f39-a8d0-c37820f30389
Truebody, Barry
dd6f5637-19bb-425a-82b6-2a273710f7ae
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Garay Baquero, Diana
da9136fe-3d47-4d04-8ab3-96bfe17a773c
Vallejo, Andres F.
294fca39-0187-47b4-90ad-cadc7b888830
Govender, Katya
b626d75a-1ecf-4b82-8cda-7cf51f19c987
Adamson, John
b0dffa81-1a4a-4867-bc8f-dc1525049b0e
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Fisher, Hayden
4ae88aa8-e168-4882-9563-3e5840b32bd6
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Steyn, Adrie
b1c3acea-9c6b-43bd-baf5-c74e384a9e5e
Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c
Ahmed, Mohamed
3e7876a3-25bb-4512-9172-b6d79a7e9516
Mackenzie, Jared
f0352cab-ab6a-40e0-98b6-970b09e9b854
Krause, Robert
c8a1efd5-d86e-4f39-a8d0-c37820f30389
Truebody, Barry
dd6f5637-19bb-425a-82b6-2a273710f7ae
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Garay Baquero, Diana
da9136fe-3d47-4d04-8ab3-96bfe17a773c
Vallejo, Andres F.
294fca39-0187-47b4-90ad-cadc7b888830
Govender, Katya
b626d75a-1ecf-4b82-8cda-7cf51f19c987
Adamson, John
b0dffa81-1a4a-4867-bc8f-dc1525049b0e
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Fisher, Hayden
4ae88aa8-e168-4882-9563-3e5840b32bd6
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Mansour, Salah
4aecba5a-8387-4f7b-b766-0a9c309ccb8b
Steyn, Adrie
b1c3acea-9c6b-43bd-baf5-c74e384a9e5e
Leslie, Alasdair
84d4f578-f3c0-46cc-9c83-a8d9bb40c38c

Ahmed, Mohamed, Mackenzie, Jared, Krause, Robert, Truebody, Barry, Tezera, Liku Bekele, Garay Baquero, Diana, Vallejo, Andres F., Govender, Katya, Adamson, John, Elkington, Paul, Fisher, Hayden, Essex, Jonathan W., Mansour, Salah, Steyn, Adrie and Leslie, Alasdair (2022) Mycobacterium tuberculosis senses host Interferon-gamma via the membrane protein MmpL10. Communications Biology. (doi:10.1101/2021.11.12.468344).

Record type: Article

Abstract

Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens and remains a leading cause of death from infectious disease. Interferon-γ (IFN-γ) is a central regulator of the immune defense against Mtb. Several cytokines have been shown to increase virulence of other bacterial pathogens, leading us to investigate whether IFN-γ has a direct effect on Mtb. We found that both recombinant and T-cell derived IFN-γ rapidly induced a dose-dependent increase in the oxygen consumption rate (OCR) of Mtb, consistent with increased bacterial respiration. This was also observed in clinical strains, but not in the vaccine strain Bacillus Calmette–Guérin (BCG), and did not occur for other cytokines tested, including TNF-α. IFN-γ binds to the cell surface of intact Mtb, but not BCG, whilst TNF-α binds to neither. Mass spectrometry analysis identified mycobacterial membrane protein large 10 (MmpL10) as the transmembrane binding partner. Consistent with this, IFN-γ binding and the OCR response was absent in a Mtb Δmmpl10 strain and restored by complementation of the mutant strain. RNA-sequencing of IFN-γ exposed Mtb revealed a distinct transcriptional profile, including genes involved in virulence and cholesterol catabolism. Finally, exposure of Mtb cells to IFN-γ resulted in sterilization of bacilli treated with isoniazid (INH), indicating clearance of phenotypically resistant bacteria that persist in the presence of INH alone. Our data suggest a novel mechanism allowing Mtb to respond to host immune activation that may be important in the immunopathogenesis of TB and have use in novel eradication strategies.

One-Sentence Summary IFN-γ is a critical component of effective immune defense in human tuberculosis yet its causative agent, Mycobacterium tuberculosis it able to sense this cytokine and increase virulence and respiration in response.

Text
2021.11.12.468344.full - Author's Original
Download (858kB)
Text
CommBio_manuscript-2022_resubmission - Accepted Manuscript
Restricted to Repository staff only
Available under License Creative Commons Attribution.
Request a copy

More information

Accepted/In Press date: 12 November 2021
Published date: 15 July 2022

Identifiers

Local EPrints ID: 471192
URI: http://eprints.soton.ac.uk/id/eprint/471192
ISSN: 2399-3642
PURE UUID: a9837e7f-908a-40d1-8d85-43750483e3d6
ORCID for Liku Bekele Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Diana Garay Baquero: ORCID iD orcid.org/0000-0002-9450-8504
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X

Catalogue record

Date deposited: 31 Oct 2022 17:42
Last modified: 01 Nov 2022 02:57

Export record

Altmetrics

Contributors

Author: Mohamed Ahmed
Author: Jared Mackenzie
Author: Robert Krause
Author: Barry Truebody
Author: Diana Garay Baquero ORCID iD
Author: Andres F. Vallejo
Author: Katya Govender
Author: John Adamson
Author: Paul Elkington ORCID iD
Author: Hayden Fisher
Author: Salah Mansour ORCID iD
Author: Adrie Steyn
Author: Alasdair Leslie

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×